The overall goal of this project is to use a multidisciplinary approach and advanced magnetic resonance imaging (MRI) to understand mechanisms that result in neurodevelopmental impairment in critically ill newborns with congenital heart disease (CHD). Data from our group and others have shown that injury to the developing brain white matter is common in newborns with CHD. The appearance of this white matter injury is identical to that seen in premature infants, with injuries identified before and after neonatal surgery. We are focusing this study on two of the most common forms of congenital heart disease: transposition of the great arteries (TGA) and single ventricle physiology (SVP), because both conditions are associated with abnormal fetal cerebral blood flow and postnatal ductal dependent circulation. We have recently determined that maturation of cerebral microstructure and metabolism are delayed in these newborns, prior to surgery, possibly as a result of impaired in utero brain development. In this proposal we will test that hypothesis that delayed in utero brain development predisposes newborns with CHD to white matter injury in response to perioperative insults. We have developed essential methods to safely measure brain development, injury and perioperative oxygen delivery in fetuses and newborns with CHD. Using these tools, we are positioned to address our overall objective of determining if delayed in utero brain development underlies the specific vulnerability of term newborns with CHD to white matter injury. To do this, we propose two specific aims: (1) To characterize brain development and injury in utero and postnatally, before and after cardiac surgery, in term newborns with TGA and SVP. (2) To determine if the risk of white matter injury is related to impaired brain oxygen delivery (proximate cause), in the setting of delayed brain microstructural and metabolic development. This multidisciplinary project combines the expertise of pediatric critical care, neurology, neuroradiology, cardiology and cardiothoracic surgery to identify specific pathophysiologic mechanisms of brain injury and develop novel prognostic measures of neurodevelopmental outcome that can be translated into future neuroprotective trials. Page McQuillen, Patrick S.